PURPOSE: Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS:A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION:Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.
RCT Entities:
PURPOSE: Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS: A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION:Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.
Authors: Juan Martin-Liberal; Antonio López-Pousa; Javier Martínez-Trufero; Javier Martín-Broto; Ricardo Cubedo; Javier Lavernia; Andrés Redondo; José Antonio López-Martín; Nùria Mulet-Margalef; Xavier Sanjuan; Òscar M Tirado; Xavier Garcia-Del-Muro Journal: Target Oncol Date: 2018-02 Impact factor: 4.493
Authors: S Chia; S Gandhi; A A Joy; S Edwards; M Gorr; S Hopkins; J Kondejewski; J P Ayoub; N Califaretti; D Rayson; S F Dent Journal: Curr Oncol Date: 2015-02 Impact factor: 3.677
Authors: Eric R Molina; Letitia K Chim; Maria C Salazar; Shail M Mehta; Brian A Menegaz; Salah-Eddine Lamhamedi-Cherradi; Tejus Satish; Sana Mohiuddin; David McCall; Ana Maria Zaske; Branko Cuglievan; Alexander J Lazar; David W Scott; Jane K Grande-Allen; Joseph A Ludwig; Antonios G Mikos Journal: Acta Biomater Date: 2019-09-19 Impact factor: 8.947
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Authors: James J Morrow; Arnulfo Mendoza; Allyson Koyen; Michael M Lizardo; Ling Ren; Timothy J Waybright; Ryan J Hansen; Daniel L Gustafson; Ming Zhou; Timothy M Fan; Peter C Scacheri; Chand Khanna Journal: Clin Cancer Res Date: 2016-06-24 Impact factor: 12.531